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Regulation of cancer cell metabolism

Rob A. Cairns*, Isaac S. Harris* and Tak W. Mak
Abstract | Interest in the topic of tumour metabolism has waxed and waned over the past
century of cancer research. The early observations of Warburg and his contemporaries
established that there are fundamental differences in the central metabolic pathways
operating in malignant tissue. However, the initial hypotheses that were based on these
observations proved inadequate to explain tumorigenesis, and the oncogene revolution
pushed tumour metabolism to the margins of cancer research. In recent years, interest has
been renewed as it has become clear that many of the signalling pathways that are affected
by genetic mutations and the tumour microenvironment have a profound effect on core
metabolism, making this topic once again one of the most intense areas of research in
cancer biology.

Redox status
Balance of the reduced state
versus the oxidized state of a
biochemical system. This
balance is influenced by the
level of reactive oxygen and
nitrogen species (ROS and
RNS) relative to the capacity of
antioxidant systems to
eliminate ROS and RNS.
The Campbell Family Cancer
Research Institute,
610 University Avenue,
Toronto, ON M56 2M9,
Canada.
*These authors contributed
equally to this work.
Correspondence to T.W.M.
e-mail:
tmak@uhnres.utoronto.ca
doi:10.1038/nrc2981
Over the past 25 years, the oncogene revolution has stim-
ulated research, revealing that the crucial phenotypes that
are characteristic of tumour cells result from a host of
mutational events that combine to alter multiple signalling
pathways. Moreover, high-throughput sequencing data
suggest that the mutations leading to tumorigenesis are
even more numerous and heterogeneous than previously
thought1,2. It is now clear that there are thousands of point
mutations, translocations, amplifications and deletions
that may contribute to cancer development, and that the
mutational range can differ even among histopathologi-
cally identical tumours. Detailed bioinformatic analyses
have suggested that cancer-related driver mutations affect
a dozen or more core signalling pathways and processes
responsible for tumorigenesis3. These findings have led
to questions about the usefulness of targeting individual
signalling molecules as a practical therapeutic strategy.
However, it is becoming clear that many key oncogenic
signalling pathways converge to adapt tumour cell metab-
olism in order to support their growth and survival.
Furthermore, some of these metabolic alterations seem
to be absolutely required for malignant transformation.
In view of these fundamental discoveries, we propose that
alterations to cellular metabolism should be considered a
crucial hallmark of cancer.
Multiple molecular mechanisms, both intrinsic and
extrinsic, converge to alter core cellular metabolism
and provide support for the three basic needs of dividing
cells: rapid ATP generation to maintain energy status;
increased biosynthesis of macromolecules; and tightened
maintenance of appropriate cellular redox status (FIG. 1). To
meet these needs, cancer cells acquire alterations to the
metabolism of all four major classes of macromolecules:
carbohydrates, proteins, lipids and nucleic acids. Many
similar alterations are also observed in rapidly prolifer-
ating normal cells, in which they represent appropriate
responses to physiological growth signals as opposed to
constitutive cell autonomous adaptations4,5. In the case
of cancer cells, these adaptations must be implemented
in the stressful and dynamic microenvironment of the
solid tumour, where concentrations of crucial nutrients
such as glucose, glutamine and oxygen are spatially and
temporally heterogeneous6. The nature and importance
of metabolic restriction in cancer has often been masked
owing to the use of tissue culture conditions in which
both oxygen and nutrients are always in excess.
The link between cancer and altered metabolism is
not new, as many observations made during the early
period of cancer biology research identified metabolic
changes as a common feature of cancerous tissues (such
as the Warburg effect; discussed below)7. As much of the
work in the field to date has focused on rapidly prolif-
erating tumour models and cells in vitro, it is unclear to
what extent these metabolic changes are important in low-
grade slow growing tumours in which metabolic demands
are not as extreme. Future clinical data describing the
metabolic profiles of human tumours will be required to
determine which metabolic alterations are most preva-
lent in specific tumour types. However, despite the lack
of comprehensive clinical data, there has been substantial
recent progress in understanding the molecular events
that regulate some of these metabolic phenotypes.
The Warburg effect
In addition to the ATP that is required to maintain nor-
mal cellular processes, proliferating tumour cells must

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REVIEWS

At a glance function, and that aerobic glycolysis is therefore a necessary

adaptation to cope with a lack of ATP generation by oxi-
• Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core dative phosphorylation. However, it was later appreci-
cellular metabolism and provide support for the three basic needs of dividing cells: ated that mitochondrial defects are rare9 and that most
rapid ATP generation to maintain energy status; increased biosynthesis of
tumours retain the capacity for oxidative phosphorylation
macromolecules; and tightened maintenance of appropriate cellular redox status.
and consume oxygen at rates similar to those observed in
Metabolic changes are a common feature of cancerous tissues, although it is unclear
to what extent these metabolic changes are important in low-grade slow normal tissues10. In fact, mitochondrial function is crucial
growing tumours. for transformation in some systems11–13. Other explana-
• The best characterized metabolic phenotype observed in tumour cells is the Warburg
tions include the concept that glycolysis has the capacity to
effect, which is a shift from ATP generation through oxidative phosphorylation to ATP generate ATP at a higher rate than oxidative phosphory-
generation through glycolysis, even under normal oxygen concentrations. This effect lation and so would be advantageous as long as glucose
is regulated by the PI3K, hypoxia-indicible factor (HIF), p53, MYC and AMP-activated supplies are not limited. Alternatively, it has been pro-
protein kinase (AMPK)–liver kinase B1 (LKB1) pathways. posed that glycolytic metabolism arises as an adaptation
• Metabolic adaptation in tumours extends beyond the Warburg effect. It is becoming to hypoxic conditions during the early avascular phase of
clear that alterations to metabolism balance the need of the cell for energy with its tumour development, as it allows for ATP production in
equally important need for macromolecular building blocks and maintenance of the absence of oxygen. Adaptation to the resulting acidic
redox balance. To this end, a key molecule produced as a result of altered cancer microenvironment that is caused by excess lactate pro-
metabolism is reduced nicotinamide adenine dinucleotide phosphate (NADPH), duction may further drive the evolution of the glycolytic
which functions as a cofactor and provides reducing power in many enzymatic phenotype14,15. Finally, most recently, it has been proposed
reactions that are crucial for macromolecular biosynthesis. NADPH is also an that aerobic glycolysis provides a biosynthetic advantage
antioxidant and forms part of the defence against reactive oxygen species (ROS)
for tumour cells, and that a high flux of substrate through
that are produced during rapid proliferation.
glycolysis allows for effective shunting of carbon to key
• High levels of ROS can cause damage to macromolecules, which can induce
subsidiary biosynthetic pathways4,5.
senescence and apoptosis. Cells counteract the detrimental effects of ROS by
producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin
The reliance of cancer cells on increased glucose
(TRX). Several of these antioxidant systems, including GSH and TRX, rely on the uptake has proved useful for tumour detection and
reducing power of NADPH to maintain their activities. monitoring, with this phenotype serving as the basis for
• In addition to the genetic changes that alter tumour cell metabolism, the abnormal
clinical [18F]fluorodeoxyglucose positron emission tom-
tumour microenvironment — such as hypoxia, pH and low glucose concentrations — ography (FDG–PeT) imaging. FDG–PeT uses a radio-
have a major role in determining the metabolic phenotype of tumour cells. active glucose analogue to detect regions of high glucose
• Mutations in oncogenes and tumour suppressor genes cause alterations to multiple uptake, and has proved highly effective for the identifica-
intracellular signalling pathways that affect tumour cell metabolism and re-engineer tion and monitoring of many tumour types. Accordingly,
it to allow enhanced survival and growth. there is now a substantial body of useful clinical data
regarding the importance of glucose as a fuel for malig-
nancies16–19. Although there have been attempts to block
also generate the energy that is required to support rapid aerobic glycolysis in tumour cells using compounds such
cell division. Furthermore, tumour cells must evade the as 2-deoxyglucose, effective therapeutic strategies have
checkpoint controls that would normally block prolif- not yet been devised. several new therapeutic approaches
eration under the stressful metabolic conditions that are targeting numerous points in the glycolytic process are
characteristic of the abnormal tumour microenviron- currently under evaluation, including the inhibition
ment. Tumour cells reprogramme their metabolic path- of lactate dehydrogenase and the inactivation of the
ways to meet these needs during the process of tumour monocarboxylate transporters that are responsible for
progression. The best characterized metabolic phenotype conveying lactate across the plasma membrane20,21.
observed in tumour cells is the Warburg effect (FIG. 2),
which is a shift from ATP generation through oxidative The PI3K pathway. The PI3K pathway is one of the most
phosphorylation to ATP generation through glycolysis, even commonly altered signalling pathways in human can-
under normal oxygen concentrations7. As a result, unlike cers. This pathway is activated by mutations in tumour
Oxidative phosphorylation most normal cells, many transformed cells derive a sub- suppressor genes, such as PTEN, mutations in the com-
Oxygen-dependent process stantial amount of their energy from aerobic glycolysis, ponents of the PI3K complex itself or by aberrant signal-
coupling the oxidation of converting most incoming glucose to lactate rather than ling from receptor tyrosine kinases22. Once activated, the
macromolecules and the
electron transport chain with
metabolizing it in the mitochondria through oxidative PI3K pathway not only provides strong growth and sur-
ATP synthesis. In eukaryotic phosphorylation7,8. Although ATP production by glyco- vival signals to tumour cells but also has profound effects
cells, it occurs within the lysis can be more rapid than by oxidative phosphorylation, on their metabolism. Indeed, it seems that the integra-
mitochondria and is a source of it is far less efficient in terms of ATP generated per unit tion of growth and proliferation signals with alterations
ROS production.
of glucose consumed. This shift therefore demands that to central metabolism is crucial for the oncogenic effects
Glycolysis tumour cells implement an abnormally high rate of glu- of this signalling pathway 23.
Oxygen-independent cose uptake to meet their increased energy, biosynthesis The best-studied effector downstream of PI3K is
metabolism of glucose and and redox needs. AKT1 (also known as PKb). AKT1 is an important
other sugars into pyruvate to There is some debate about the most important selec- driver of the tumour glycolytic phenotype and stimulates
produce energy in the form of
ATP and intermediate
tive advantage that glycolytic metabolism provides to ATP generation through multiple mechanisms, ensur-
substrates for other metabolic proliferating tumour cells. Initial work focused on the con- ing that cells have the bioenergetic capacity required to
pathways. cept that tumour cells develop defects in mitochondrial respond to growth signals24,25. AKT1 stimulates glycolysis

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by increasing the expression and membrane transloca-
tion of glucose transporters and by phosphorylating key
glycolytic enzymes, such as hexokinase and phospho-
fructokinase 2 (also known as PFKFb3)24,26 (FIG. 2). The
increased and prolonged AKT1 signalling that is asso-
ciated with transformation inhibits forkhead box sub-
family O (FOXO) transcription factors, resulting in a host
of complex transcriptional changes that increase glyco-
lytic capacity 27. AKT1 also activates ectonucleoside tri-
phosphate diphosphohydrolase 5 (enTPD5), an enzyme
that supports increased protein glycosylation in the
endoplasmic reticulum and indirectly increases glyco-
lysis by creating an ATP hydrolysis cycle28. Finally, AKT1
strongly stimulates signalling through the kinase mTOr
by phosphorylating and inhibiting its negative regulator
tuberous sclerosis 2 (TsC2; also known as tuberin)26.
mTOr functions as a key metabolic integration point,
coupling growth signals to nutrient availability. Activated
mTOr stimulates protein and lipid biosynthesis and cell
growth in response to sufficient nutrient and energy
conditions and is often constitutively activated during
tumorigenesis29. At the molecular level, mTOr directly
stimulates mrnA translation and ribosome biogenesis,
and indirectly causes other metabolic changes by acti-
vating transcription factors such as hypoxia-inducible
factor 1 (HIF1) even under normoxic conditions.
The subsequent HIF1-dependent metabolic changes
are a major determinant of the glycolytic phenotype
downstream of PI3K, AKT1 and mTOr (FIG. 2).
HIF1 and MYC. The HIF1 and HIF2 complexes are the
major transcription factors that are responsible for gene
expression changes during the cellular response to low
oxygen conditions. They are heterodimers that are com-
posed of the constitutively expressed HIF1β (also known
as ArnT) subunit, and either the HIF1α or the HIF2α
(also known as ePAs1) subunits, which are rapidly
stabilized on exposure to hypoxia30. under normoxic
Genetic alterations Tumour microenvironment
(affecting p53, MYC, (hypoxia, pH, nutrients
AMPK, PI3K and HIF1) and autophagy)
Abnormal
metabolic
phenotype
Bioenergetics Biosynthesis Redox
Figure 1 | Determinants of the tumour metabolic phenotype.Nature Reviews | Cancer
The metabolic
phenotype of tumour cells is controlled by intrinsic genetic mutations and external
responses to the tumour microenvironment. Oncogenic signalling pathways controlling
growth and survival are often activated by the loss of tumour suppressors (such as p53) or
the activation of oncoproteins (such as PI3K). The resulting altered signalling modifies
cellular metabolism to match the requirements of cell division. Abnormal
microenvironmental conditions such as hypoxia, low pH and/or nutrient deprivation
elicit responses from tumour cells, including autophagy, which further affect metabolic
activity. These adaptations optimize tumour cell metabolism for proliferation by
providing appropriate levels of energy in the form of ATP, biosynthetic capacity and the
maintenance of balanced redox status. AMPK, AMP-activated protein kinase; HIF1,
hypoxia-inducible factor 1.
nATure revIeWs | CanCer
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
conditions, the HIFα subunits undergo oxygen-dependent
hydroxylation by prolyl hydroxylase enzymes, which
results in their recognition by von Hippel–lindau
tumour suppressor (vHl), an e3 ubiquitin ligase,
and subsequent degradation. HIF1α is ubiquitously
expressed, whereas the expression of HIF2α is restricted
to a more limited subset of cell types30. Although these
two transcription factors transactivate an overlapping set
of genes, the effects on central metabolism have been bet-
ter characterized for HIF1, and therefore our discussion
is limited to HIF1 specifically.
In addition to its stabilization under hypoxic con-
ditions, HIF1 can also be activated under normoxic
conditions by oncogenic signalling pathways, including
PI3K23,31, and by mutations in tumour suppressor pro-
teins such as vHl32,33, succinate dehydrogenase (sDH)34
and fumarate hydratase (FH)35. Once activated, HIF1
amplifies the transcription of genes encoding glucose
transporters and most glycolytic enzymes, increasing
the capacity of the cell to carry out glycolysis36. In addi-
tion, HIF1 activates the pyruvate dehydrogenase kinases
(PDKs), which inactivate the mitochondrial pyruvate
dehydrogenase complex and thereby reduce the flow
of glucose-derived pyruvate into the tricarboxylic acid
(TCA) cycle37–39 (FIG. 2). This reduction in pyruvate flux
into the TCA cycle decreases the rate of oxidative phos-
phorylation and oxygen consumption, reinforcing the
glycolytic phenotype and sparing oxygen under hypoxic
conditions.
Inhibitors of HIF1 or the PDKs could potentially
reverse some of the metabolic effects of tumorigenic HIF1
signalling and several such candidates, including the PDK
inhibitor dichloroacetic acid (DCA), are currently under
evaluation for their therapeutic utility 40–43.
In addition to its well-described role in controlling
cell growth and proliferation, the oncogenic transcrip-
tion factor MyC also has several important effects on cell
metabolism44. With respect to glycolysis, highly expressed
oncogenic MyC has been shown to collaborate with HIF
in the activation of several glucose transporters and
glycolytic enzymes, as well as lactate dehydrogenase A
(lDHA) and PDK1 (ReFS 45,46). However, MyC also
activates the transcription of targets that increase mito-
chondrial biogenesis and mitochondrial function, espe-
cially the metabolism of glutamine, which is discussed
in further detail below 47.
AMP-activated protein kinase. AMP-activated protein
kinase (AMPK) is a crucial sensor of energy status and
has an important pleiotropic role in cellular responses
to metabolic stress. The AMPK pathway couples energy
status to growth signals; biochemically, AMPK opposes
the effects of AKT1 and functions as a potent inhibitor
of mTOr (FIG. 2). The AMPK complex thus functions as
a metabolic checkpoint, regulating the cellular response
to energy availability. During periods of energetic stress,
AMPK becomes activated in response to an increased
AMP/ATP ratio, and is responsible for shifting cells to an
oxidative metabolic phenotype and inhibiting cell prolif-
eration48–50. Tumour cells must overcome this checkpoint
in order to proliferate in response to activated growth
vOluMe 11 | FebruAry 2011 | 87
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signalling pathways, even in a less than ideal microen- activated by oncogenes and the loss of tumour sup-
vironment 49. several oncogenic mutations and signal- pressors. Accordingly, many cancer cells exhibit a loss
ling pathways can suppress AMPK signalling 49, which of appropriate AMPK signalling: an event that may also
uncouples fuel signals from growth signals, allowing contribute to their glycolytic phenotype.
tumour cells to divide under abnormal nutrient condi- Given the role of AMPK, it is not surprising that
tions. This uncoupling permits tumour cells to respond STK11, which encodes liver kinase b1 (lKb1) — the
to inappropriate growth signalling pathways that are upstream kinase necessary for AMPK activation —
has been identified as a tumour suppressor gene and is
mutated in Peutz–Jeghers syndrome51. This syndrome
a Quiescent normal cell
is characterized by the development of benign gastro-
Lactate Glucose intestinal and oral lesions and an increased risk of
developing a broad range of malignancies. lKb1 is also
MCT GLUT
frequently mutated in sporadic cases of non-small-cell
Glucose lung cancer 52 and cervical carcinoma53. recent evidence
PI3K p53 LKB1
suggests that lKb1 mutations are tumorigenic owing to
Glycolysis PTEN the resulting decrease in AMPK signalling and loss of
AKT AMPK mTOr inhibition49. The loss of AMPK signalling allows
Lactate Pyruvate the activation of mTOr and HIF1, and therefore might
mTOR also support the shift towards glycolytic metabolism.
Clinically, there is currently considerable interest in eval-
TIGAR PDH PDK
uating whether AMPK agonists can be used to re-couple
p53 OCT1 MYC HIF fuel and growth signals in tumour cells and to shut down
Acetyl-CoA TCA
SCO2 cell growth. Two such agonists are the commonly used
antidiabetic drugs metformin and phenformin49,54–56. It
remains to be seen whether these agents represent a useful
b Proliferating tumour cell class of metabolic modifiers with antitumour activity.
Lactate Glucose
p53 and OCT1. Although the transcription factor and
GLUT tumour suppressor p53 is best known for its functions
MCT
in the DnA damage response (DDr) and apoptosis, it is
Glucose PI3K p53 LKB1 becoming clear that p53 is also an important regulator of
metabolism57. p53 activates the expression of hexokinase 2
PTEN
Glycolysis (HK2), which converts glucose to glucose-6-phosphate
AKT AMPK (G6P)58. G6P then either enters glycolysis to produce
PKM2
ATP, or enters the pentose phosphate pathway (PPP),
mTOR
Lactate Pyruvate which supports macromolecular biosynthesis by produc-
ing reducing potential in the form of reduced nicotina-
TIGAR PDH PDK mide adenine dinucleotide phosphate (nADPH) and/or
ribose, the building blocks for nucleotide synthesis.
p53 OCT1 MYC HIF
Acetyl-CoA TCA However, p53 inhibits the glycolytic pathway by upreg-
SCO2 ulating the expression of TP53-induced glycolysis and
apoptosis regulator (TIGAr), an enzyme that decreases
Figure 2 | Molecular mechanisms driving the Warburg effect. Relative to normal cells the levels of the glycolytic activator fructose-2,6-
Nature
(part a) the shift to aerobic glycolysis in tumour cells (part b) is driven Reviews | Cancer
by multiple bisphosphate59 (FIG. 2). Wild-type p53 also supports the
oncogenic signalling pathways. PI3K activates AKT, which stimulates glycolysis by directly expression of PTen, which inhibits the PI3K pathway,
regulating glycolytic enzymes and by activating mTOR. The liver kinase B1 (LKB1) tumour
thereby suppressing glycolysis (as discussed above)60.
suppressor, through AMP-activated protein kinase (AMPK) activation, opposes the
glycolytic phenotype by inhibiting mTOR. mTOR alters metabolism in a variety of ways, Furthermore, p53 promotes oxidative phosphorylation
but it has an effect on the glycolytic phenotype by enhancing hypoxia-inducible factor 1 by activating the expression of sCO2, which is required
(HIF1) activity, which engages a hypoxia-adaptive transcriptional programme. HIF1 for the assembly of the cytochrome c oxidase complex
increases the expression of glucose transporters (GLUT), glycolytic enzymes and pyruvate of the electron transport chain61. Thus, the loss of p53
dehydrogenase kinase, isozyme 1 (PDK1), which blocks the entry of pyruvate into the might also be a major force behind the acquisition of the
tricarboxylic acid (TCA) cycle. MYC cooperates with HIF in activating several genes that glycolytic phenotype.
encode glycolytic proteins, but also increases mitochondrial metabolism. The tumour OCT1 (also known as POu2F1) is a transcription
suppressor p53 opposes the glycolytic phenotype by suppressing glycolysis through factor, the expression of which is increased in several
TP53-induced glycolysis and apoptosis regulator (TIGAR), increasing mitochondrial human cancers, and it may cooperate with p53 in regu-
metabolism via SCO2 and supporting expression of PTEN. OCT1 (also known as POU2F1)
lating the balance between oxidative and glycolytic
acts in an opposing manner to activate the transcription of genes that drive glycolysis and
suppress oxidative phosphorylation. The switch to the pyruvate kinase M2 (PKM2) isoform metabolism62–64. The transcriptional programme that is
affects glycolysis by slowing the pyruvate kinase reaction and diverting substrates into initiated by OCT1 supports resistance to oxidative stress
alternative biosynthetic and reduced nicotinamide adenine dinucleotide phosphate and this may cooperate with the loss of p53 during trans-
(NADPH)-generating pathways. MCT, monocarboxylate transporter; PDH, pyruvate formation64. Data from studies of knockout mice and
dehydrogenase. The dashed lines indicate loss of p53 function. human cancer cell lines show that OCT1 regulates a set

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Pentose phosphate pathway
PPP. Biochemical pathway
converting glucose into
substrates for nucleotide
biosynthesis and redox control,
such as ribose and NADPH.
Owing to multiple connections
to the glycolytic pathway, the
PPP can operate in various
modes to allow the production
of NADPH and/or ribose as
required.
Macromolecular
biosynthesis
Biochemical synthesis of the
carbohydrates, nucleotides,
proteins and lipids that make
up cells and tissues. These
pathways require energy,
reducing power and
appropriate substrates.
Reduced nicotinamide
adenine dinucleotide
phosphate
NADPH. Cofactor that drives
anabolic biochemical reactions
and provides reducing capacity
to combat oxidative stress.
nATure revIeWs | CanCer
of genes that increase glucose metabolism and reduce
mitochondrial respiration. One of these genes encodes
an isoform of PDK (PDK4) that has the same function
as the PDK enzymes that are activated by HIF1 (ReF. 64)
(FIG. 2). Although the mechanisms by which OCT1 is
upregulated in tumour cells are poorly understood,
its downstream effectors may be potential targets for
therapeutic intervention.
Beyond the Warburg effect
Metabolic adaptation in tumours extends beyond the
Warburg effect. It is becoming clear that alterations to
metabolism balance the need of the cell for energy with
its equally important need for macromolecular building
blocks and maintenance of redox balance.
Pyruvate kinase (PK). As previously discussed, the gen-
eration of energy in the form of ATP through aerobic
glycolysis is required for unrestricted cancer cell pro-
liferation7. However, studies of the M2 isoform of PK
(PKM2) have shown that ATP generation by aerobic
glycolysis is not the sole metabolic requirement of a
cancer cell, and that alterations to metabolism not only
bolster ATP resources but also stimulate macromolecular
biosynthesis and redox control.
PK catalyses the rate-limiting, ATP-generating step of
glycolysis in which phosphoenolpyruvate (PeP) is con-
verted to pyruvate65. Multiple isoenzymes of PK exist in
mammals: type l, which is found in the liver and kid-
neys; type r, which is expressed in erythrocytes; type
M1, which is found in tissues such as muscle and brain;
and type M2, which is present in self-renewing cells such
as embryonic and adult stem cells65. Intriguingly, PKM2
is also expressed by many tumour cells. Furthermore,
it was discovered that although PKM1 could efficiently
promote glycolysis and rapid energy generation, PKM2
is characteristically found in an inactive state and is
ineffective at promoting glycolysis66–68.
This observation was ignored by the scientific com-
munity for several years owing to its shear counterin-
tuitive nature: a tumour-specific glycolytic enzyme that
inhibits ATP generation and antagonizes the Warburg
effect. Only on closer examination of the full metabolic
requirements of a cancer cell was the advantage of PKM2
expression revealed. A cancer cell, like any normal cell,
must obtain the building blocks that are required for the
synthesis of lipids, nucleotides and amino acids. Without
sufficient precursors available for this purpose, rapid cell
proliferation will halt, no matter how vast a supply of
ATP is present. PKM2 provides an advantage to cancer
cells because, by slowing glycolysis, this isozyme allows
carbohydrate metabolites to enter other subsidiary
pathways, including the hexosamine pathway, uridine
diphosphate (uDP)–glucose synthesis, glycerol syn-
thesis and the PPP, which generate macromolecule
precursors, that are necessary to support cell prolif-
eration, and reducing equivalents such as nADPH4,28,69
(FIG. 3). subsequent studies have confirmed that PKM2
expression by lung cancer cells confers a tumorigenic
advantage over cells expressing the PKM1 isoform70.
Interestingly, the classical oncoprotein MyC has been
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
Glucose
PPP
NADPH
G6P
Glycolysis Macromolecules
PEP
ATP PKM2
Pyruvate
Figure 3 | PKM2 and its effect on glycolysis and the
pentose phosphate pathway. Pyruvate Naturekinase
Reviews | Cancer
isoform
M2 (PKM2) is present in very few types of proliferating
normal cells but is present at high levels in cancer cells.
PKM2 catalyses the rate-limiting step of glycolysis,
controlling the conversion of phosphoenolpyruvate (PEP)
to pyruvate, and thus ATP generation. Although
counterintuitive, PKM2 opposes the Warburg effect by
inhibiting glycolysis and the generation of ATP in tumours.
Although such an effect might at first seem to be
detrimental to tumour growth, the opposite is true. By
slowing the passage of metabolites through glycolysis,
PKM2 promotes the shuttling of these substrates through
the pentose phosphate pathway (PPP) and other
alternative pathways so that large quantities of reduced
nicotinamide adenine dinucleotide phosphate (NADPH)
and other macromolecules are produced. These molecules
are required for macromolecule biosynthesis and the
maintenance of redox balance that is needed to support
the rapid cell division that occurs within a tumour. G6P,
glucose-6-phosphate.
found to promote preferential expression of PKM2 over
PKM1 by modulating exon splicing. The inclusion of
exon 9 in the PK mrnA leads to translation of the PKM1
isoform, whereas inclusion of exon 10 produces PKM2
(ReF. 71). MyC upregulates the expression of heteroge-
neous nuclear ribonucleoproteins (hnrnPs) that bind
to exon 9 of the PK mrnA and lead to the preferen-
tial inclusion of exon 10 and thus to the predominant
production of PKM2. by promoting PKM2 expression,
MyC promotes the production of nADPH in order to
match the increased ATP production and to satisfy the
auxiliary needs required for increased proliferation.
At the clinical level, increased PKM2 expression has
been documented in patient samples of various cancer
types, leading to the proposal that PKM2 might be a use-
ful biomarker for the early detection of tumours65,72–74.
However, further study of the prevalence of PKM2 in
cancers and the effect of PKM2 on tumorigenesis is still
required.
NADPH. A key molecule produced as a result of the
promotion of the oxidative PPP by PKM2 is nADPH
(FIG. 4). nADPH functions as a cofactor and provides
reducing power in many enzymatic reactions that are
crucial for macromolecular biosynthesis. Although
other metabolites are produced as a result of increased
PPP activity, including ribose, which can be converted
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REVIEWS
Glucose Isocitrate Malate Glutamine
IDH1 or
ME1
IDH2
G6P αKG Pyruvate Glutamate
PPP
MYC Glutaminolysis
PKM2
MYC NADPH GSH
Redox control
Figure 4 | Mechanisms of redox control and their alterationsNaturein cancer. The| Cancer
Reviews
production of two of the most abundant antioxidants, reduced nicotinamide adenine
dinucleotide phosphate (NADPH) and glutathione (GSH), has been shown to be
modulated in cancers. Pyruvate kinase isoform M2 (PKM2), which is overexpressed in
many cancer cells, can divert metabolic precursors away from glycolysis and into the
pentose phosphate pathway (PPP) to produce NADPH. NADP-dependent isocitrate
dehydrogenase 1 (IDH1), IDH2 and malic enzyme 1 (ME1) also contribute to NADPH
production. MYC increases glutamine uptake and glutaminolysis, driving the de novo
synthesis of GSH. Additionally, MYC contributes to NADPH production by promoting the
expression of PKM2. Together, NADPH and GSH control increased levels of reactive
oxygen species (ROS) driven by increased cancer cell proliferation. αKG, α-ketoglutarate;
G6P, glucose-6-phosphate.
into nucleotides, the supply of these building blocks
may not be as important as the production of nADPH.
not only does nADPH fuel macromolecular biosyn-
thesis, but it is also a crucial antioxidant, quenching the
reactive oxygen species (rOs) produced during rapid
cell proliferation. In particular, nADPH provides the
reducing power for both the glutathione (GsH) and
thioredoxin (TrX) systems that scavenge rOs
and repair rOs-induced damage75. The double-pronged
importance of nADPH in cancer cell metabolism has
prompted proposals of clinical intervention by inhibit-
ing nADPH production. Attenuation of the PPP would
theoretically dampen nADPH production in cancer cells,
slowing macromolecular biosynthesis and rendering the
transformed cells vulnerable to free radical-mediated
damage. In this way, the advantage conferred by PKM2
expression would be eliminated. In preclinical studies,
drugs such as 6-amino-nicotinamide (6-An), which
inhibits G6P dehydrogenase (G6PD; the enzyme that
initiates the PPP) have demonstrated anti-tumorigenic
effects in leukaemia, glioblastoma and lung cancer cell
lines76. However, additional basic research and complete
clinical trials will be required to properly assess their
therapeutic potential.
The discovery and subsequent investigation of the
2‑hydroxyglutarate effects of PKM2 expression has shown that we must
2-HG. A dicarboxylic acid construct a post-Warburg model of cancer metabo-
metabolite produced from αKG lism, in which ATP generation is not the sole metabolic
by the NADPH-dependent requirement of tumour cells. This turning point has led
reaction of the mutated forms
of IDH1 and IDH2. It is also
to the realization that the metabolic alterations present
produced at low levels by other in cancer cells promote not only ATP resources, but also
enzymes. macromolecular biosynthesis and redox control (FIG. 1).
90 | FebruAry 2011 | vOluMe 11
© 2011 Macmillan Publishers Limited. All rights reserved
Isocitrate dehydrogenases. Another mechanism by
which nADPH is produced in mammalian cells is the
reaction converting isocitrate to α-ketoglutarate (αKG),
which is catalysed by nADP-dependent isocitrate dehy-
drogenase 1 (IDH1) and IDH2. IDH1 and IDH2 are
homodimeric enzymes that act in the cytoplasm and
mitochondria, respectively, to produce nADPH by this
reaction. IDH1 and IDH2 are highly homologous and
structurally and functionally distinct from the nAD-
dependent enzyme IDH3, which functions in the TCA
cycle to produce the nADH that is required for oxidative
phosphorylation.
It has recently been found that specific mutations
in IDH1 and IDH2 are linked to tumorigenesis. Two
independent cancer genome sequencing projects iden-
tified driver mutations in IDH1 in glioblastoma and
acute myeloid leukaemia (AMl)3,77. subsequent stud-
ies revealed that IDH1 or IDH2 is mutated in approxi-
mately 80% of adult grade II and grade III gliomas and
secondary glioblastomas, and in approximately 30% of
cytogenetically normal cases of AMl78–80. The IDH1 and
IDH2 mutations associated with the development of
glioma and AMl are restricted to crucial arginine resi-
dues required for isocitrate binding in the active site of
the protein: r132 in IDH1, and r172 and r140 in IDH2
(ReFS 3,77,79,80). Affected patients are heterozygous for
these mutations, suggesting that these alterations may
cause an oncogenic gain-of-function. The range of muta-
tions differs in the two diseases, with the IDH1 r132H
mutation predominating in gliomas (>90%), whereas a
more diverse collection of mutations in both IDH1 and
IDH2 are found in AMl4,78–80.
It was initially proposed that these mutations might
act through dominant-negative inhibition of IDH1
and IDH2 activity, which could lead to a reduction in
cytoplasmic αKG concentration, inhibition of prolyl
hydroxylase activity and stabilization of HIF1 (ReF. 81).
However, it has recently been shown that these muta-
tions cause IDH1 and IDH2 to acquire a novel enzy-
matic activity that converts αKG to 2-hydroxyglutarate
(2-HG) in a nADPH-dependent manner 79,80,82 (FIG. 5).
In fact, this change causes the mutated IDH1 and IDH2
enzymes to switch from nADPH production to nADPH
consumption, with potentially important consequences
for the cellular redox balance. The product of the novel
reaction, 2-HG, is a poorly understood metabolite. 2-HG
is present at low concentrations in normal cells and
tissues. However, in patients with somatic IDH1 or IDH2
mutations, 2-HG builds up to high levels in glioma tis-
sues, and in the leukaemic cells and sera of patients with
AMl79,80,82. It remains to be determined whether these
high concentrations of 2-HG are mechanistically respon-
sible for the ability of IDH1 and IDH2 mutations to drive
tumorigenesis. Importantly, levels of αKG, isocitrate and
several other TCA metabolites are not altered in cell
lines or tissues expressing IDH1 mutations, suggesting
that other metabolic pathways can adjust and maintain
normal levels of these essential metabolites79,82.
studies of IDH1 and IDH2 have established a new
paradigm in oncogenesis: a driver mutation that con-
fers a new metabolic enzymatic activity that produces a
www.nature.com/reviews/cancer

potential oncometabolite. The molecular mechanisms by
which IDH1 and IDH2 mutations contribute to tumori-
genesis are still under investigation, as is the possibil-
ity that these mutant enzymes may be useful targets for
therapy. Curiously, although IDH1 and IDH2 mutations
are clearly powerful drivers of glioma and AMl, they
seem to be rare or absent in other tumour types78,83,84.
This observation highlights the importance of the
specific cellular context in understanding metabolic
perturbations in cancer cells.
Metabolic alterations supporting redox status
rOs are a diverse class of radical species that are pro-
duced in all cells as a normal byproduct of metabolic
processes. rOs are heterogeneous in their properties
and have a plethora of downstream effects, depending
on the concentrations at which they are present.
At low levels, rOs increase cell proliferation and
survival through the post-translational modification of
kinases and phosphatases85–87. The production of this
low level of rOs can be driven by nADPH and nADPH
oxidase (nOX) and is required for homeostatic signal-
ling events. At moderate levels, rOs induce the expres-
sion of stress-responsive genes such as HIF1Α, which in
turn trigger the expression of proteins providing pro-
survival signals, such as the glucose transporter GluT1
(also known as slC2A1) and vascular endothelial
growth factor (veGF)88,89. However, at high levels, rOs
can cause damage to macromolecules, including DnA;
induce the activation of protein kinase Cδ (PKCδ), trig-
gering senescence90,91; and/or cause permeabilization of
the mitochondria, leading to the release of cytochrome c
and apoptosis92,93. Cells counteract the detrimental
effects of rOs by producing antioxidant molecules,
such as reduced GsH and TrX. These molecules reduce
excessive levels of rOs to prevent irreversible cellular
damage94. Importantly, several of these antioxidant sys-
tems, including GsH and TrX, rely on the reducing
power of nADPH to maintain their activities. In highly
Glucose Acetyl-CoA Fatty acids
Lactate Pyruvate Citrate Isocitrate
NADP
IDH1 or
Acetyl-CoA IDH2
TCA NADPH NADP
αKG 2-HG
IDH1 mutant or
Glutamine or glutamate IDH2 mutant
Figure 5 | IDH1 and IDH2 mutations cause an oncometabolic gain of function.
Nature
Certain somatic mutations at crucial arginine residues in isocitrate Reviews | Cancer
dehydrogenase 1 malignant cells might be selectively killed109–111.
(IDH1, which is cytoplasmic) and IDH2 (which is mitochondrial) are common early driver
mutations in glioma and acute myeloid leukaemia (AML). These mutations are unusual
because they cause the gain of a novel enzymatic activity. Instead of isocitrate being
converted to α-ketoglutarate (αKG) with the production of reduced nicotinamide
adenine dinucleotide phosphate (NADPH), αKG is converted to 2-hydroxyglutarate
(2-HG) with the consumption of NADPH. 2-HG builds up to high levels in tumour cells
and tissues of affected patients and supports tumour progression by a mechanism that is
yet to be determined. TCA, tricarboxylic acid cycle.
nATure revIeWs | CanCer
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
proliferative cancer cells, rOs regulation is crucial owing
to the presence of oncogenic mutations that promote
aberrant metabolism and protein translation, result-
ing in increased rates of rOs production. Transformed
cells counteract this accumulation of rOs by further
upregulating antioxidant systems, seemingly creating a
paradox of high rOs production in the presence of high
antioxidant levels95–98 (FIG. 6).
RB, PTEN and p53. There is currently a scientific con-
sensus that cancer cells alter their metabolic pathways
and regulatory mechanisms so that rOs and antioxi-
dants are tightly controlled and maintained at higher
levels than in normal cells. However, during the process
of tumorigenesis, loss of tumour suppressors may cause
cells to become overloaded with the products of aberrant
metabolism and lose control of redox balance. For exam-
ple, when the tumour suppressor TSC2 is deleted, mTOr
becomes hyperactivated99. Hyperactivated mTOr leads
to an upregulation of translation and increased rOs
production100. In a cancer cell that has additionally lost
function of the tumour suppressor retinoblastoma (rb),
which normally participates in the antioxidant response,
the increased rOs production is not countered and the
cell will undergo apoptosis99. similar results have been
seen with loss of PTen, and hyperactivation of AKT1
leads to FOXO inactivation and increased oxidative
stress101.
A comparable theory can be proposed for p53. p53
may promote oxidative stress while inducing apopto-
sis102–104, but it also has an important role in reducing oxi-
dative stress as a defence mechanism105,106. Glutaminase 2
(Gls2) is upregulated by p53 and drives de novo synthesis
of GsH107. Furthermore, through the p53 target gene
cyclin-dependent kinase inhibitor 1A (CDKN1A, which
encodes p21), p53 promotes the stabilization of the trans-
cription factor nrF2 (also known as nFe2l2)108. nrF2
is the master antioxidant transcription factor and upreg-
ulates the expression of several antioxidant and detoxify-
ing molecules108. When rOs levels are low, nrF2 binds
to kelch-like eCH-associated protein 1 (KeAP1), which
triggers nrF2 degradation. under oxidative stress, p53 is
activated and stimulates expression of p21. p21 prevents
the KeAP1–nrF2 interaction and preserves nrF2,
driving antioxidant countermeasures108. loss of p53 in
a cancer cell inactivates this redox maintenance mecha-
nism: because p21 is not activated, nrF2 continues to be
degraded, antioxidant proteins are not expressed and the
redox balance is lost. From a clinical point of view, it may
be possible to exploit loss-of-function p53 mutations or
other tumour suppressor genes by applying additional
oxidative stress. In the absence of the redox maintenance
pathway that is supported by these tumour suppressors,
DJ1. Much of the research involving rOs and oxidative
stress has emerged from work in the field of neurode-
generative diseases. Only recently has it been realized
that similar mechanisms maintain appropriate redox
status in both normal neurons and cancer cells. One
protein involved in preventing neurodegeneration that
vOluMe 11 | FebruAry 2011 | 91
REVIEWS

• Proliferation • Adaptive genes • Senescence cancers. Additional investigation of the cancer risk of
• Cell survival • Mutagenesis • Cell death patients with other neurodegenerative disorders, such as
Als, may provide key insights into potential therapeutic

ROS level
exploitation of the heightened need to maintain redox
balance in a cancer cell.
Cancer cell
Glutamine and MYC. It has long been known that cell
• Metabolism culture medium must be supplemented with high con-
• Protein translation Antioxidants
centrations of glutamine to support robust cell prolif-
eration120–122. However, it has recently been shown that
Figure 6 | relationship between the levels of rOS and cancer. Nature
TheReviews
effect of| Cancer transformation stimulates glutaminolysis and that many
reactive oxygen species (ROS) on cell fate depends on the level at which ROS are tumour cells are critically dependent on this amino
present. Low levels of ROS (yellow) provide a beneficial effect, supporting cell acid123,124. After glutamine enters the cell, glutaminase
proliferation and survival pathways. However, once levels of ROS become excessively enzymes convert it to glutamate, which has several fates.
high (purple), they cause detrimental oxidative stress that can lead to cell death. To Glutamate can be converted directly into GsH by the
counter such oxidative stress, a cell uses antioxidants that prevent ROS from enzyme glutathione cysteine ligase (GCl) (FIG. 4). reduced
accumulating at high levels. In a cancer cell, aberrant metabolism and protein
GsH is one of the most abundant antioxidants found in
translation generate abnormally high levels of ROS. Through additional mutations and
adaptations, a cancer cell exerts tight regulation of ROS and antioxidants in such a way mammalian cells and is vital to controlling the redox state
that the cell survives and the levels of ROS are reduced to moderate levels (blue). This of all subcellular compartments97. Glutamate can also be
extraordinary control of ROS and the mechanisms designed to counter it allow the converted to αKG and enter the TCA cycle. This pro-
cancer cell to avoid the detrimental effects of high levels of ROS, but also increase the cess of anapleurosis supplies the carbon input required
chance that the cell will experience additional ROS-mediated mutagenic events and for the TCA cycle to function as a biosynthetic ‘hub’ and
stress responses that promote tumorigenesis. Figure inspired by discussions with permits the production of other amino acids and fatty
Navdeep Chandel, Northwestern University, Chicago, USA. acids. There is also recent evidence that some glutamine-
derived carbon can exit the TCA cycle as malate and
serve as a substrate for malic enzyme 1 (Me1), which
has also been investigated in the context of cancer is DJ1 produces nADPH125. The precise mechanisms regulating
(also known as PArK7). similar to p21, DJ1 stabilizes the fate of glutamine in tumour cells are not completely
nrF2 and thereby promotes antioxidant responses112. understood, and it is likely that genetic background and
DJ1 is mutated and inactive in several neurodegenera- microenvironmental factors have a role.
tive disorders, most notably Parkinson’s disease113. In One factor that is known to have a major role in regu-
these disorders, it is believed that loss of DJ1 func- lating glutaminolysis is MyC, further supporting the con-
tion leads to elevated oxidative stress in the brain and cept that MyC promotes not only proliferation but also
increased neuronal cell death114. In the context of cancer, the production of accompanying macromolecules and
PARK7 has been described as an oncogene115. In patients antioxidants that are required for growth. MyC increases
Parkinson’s disease
with lung, ovarian and oesophageal cancers, high DJ1 glutamine uptake by directly inducing the expression of the
A neurodegenerative disorder
affecting the CNS, which is expression in the tumour predicts a poor outcome115–117. glutamine transporters slC5A1 and slC7A1 (also known
characterized by muscle At a mechanistic level, DJ1 stimulates AKT1 activity as CAT1)124. Furthermore, MyC indirectly increases the
rigidity and the onset of both in vitro and in vivo by regulating the function of level of glutaminase 1 (Gls1), the first enzyme of glutami-
tremors. the tumour suppressor PTen115. Although this func- nolysis, by repressing the expression of microRNA‑23A
Amyotrophic lateral
tion seems to be a logical candidate for the mechanism and microRNA‑23B, which inhibit GLS1 (ReF. 124). Thus,
sclerosis underlying the tumorigenic role of DJ1, high DJ1 expres- MyC may support antioxidant capacity by driving PPP-
ALS. Also known as Lou sion may also promote tumorigenesis by reducing the based nADPH production through promoting the expres-
Gehrig’s disease; it occurs oxidative stress caused by aberrant cell proliferation and sion of the PKM2 isoform, as described above, and also by
owing to the degeneration of
thereby prevent rOs-induced cell death. increasing the synthesis of GsH through glutaminolysis
the CNS and leads to the
inability to control muscles and several other proteins that are inactivated in neuro- (FIG. 4). A comprehensive and quantitative investigation
eventual muscle atrophy. degenerative disorders have antioxidant properties, of glutamine metabolism in patient samples has not yet
including the enzyme superoxide dismutase 1 (sOD1). been reported. However, new techniques for measuring
Glutaminolysis Mutations in sOD1 are responsible for 20% of familial glutamine and its metabolites have been developed and
The catabolic metabolism of
glutamine, which yields
cases of amyotrophic lateral sclerosis (Als)118. However, it should soon permit the detailed examination of glutamine
substrates that replenish the is still unknown whether sOD1 or other key antioxidant metabolism and MyC expression in patient tumours126.
TCA cycle, produce GSH and enzymes are hyperactivated in cancer cells and whether Furthermore, work is underway to determine whether
supply building blocks for they have important roles in tumorigenesis. supporting other oncoproteins such as PI3K and srC have a role in
amino acid and nucleotide
the notion that loss of DJ1 prevents appropriate redox promoting glutaminolysis. supporting this theory, it has
synthesis.
control in cancers, an inverse correlation has been been shown that cells with a hyperactive ras oncogene
Anapleurosis reported between cancer risk and Parkinson’s disease. A require a stable flow of glutamine and GsH generation in
Category of reactions that recent meta-analysis of patients with Parkinson’s disease order to balance redox demands13,111. It is also interesting
serve to replenish the determined that they have an approximately 30% lower to speculate that part of the mechanism responsible for the
intermediate substrates of an
anabolic biochemical pathway,
risk of developing cancers compared with controls119. clinical efficacy of l-asparaginase in treating certain leu-
especially important in the TCA This lower risk was associated with several different kaemias may be related to this phenomenon, as l-aspara-
cycle. cancer types, including lung, prostate and colorectal ginase therapy reduces serum levels of both asparagine and

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© 2011 Macmillan Publishers Limited. All rights reserved


glutamine127,128. nevertheless, several questions regarding
the role of glutamine in tumorigenesis remain to be
answered.
Metabolic adaptation to the microenvironment
In addition to the genetic changes that alter tumour cell
metabolism, the abnormal tumour microenvironment has
a major role in determining the metabolic phenotype of
tumour cells. Tumour vasculature is structurally and func-
tionally abnormal, and combined with intrinsically altered
tumour cell metabolism, creates spatial and temporal het-
erogeneity in oxygenation, pH, and the concentrations of
glucose and many other metabolites. These extreme con-
ditions induce a collection of cellular stress responses that
further contribute to the distorted metabolic phenotype of
tumour cells and influence tumour progression129.
Response to hypoxia. The response to hypoxia is the best
studied of tumour cell stress responses owing to the well-
known effects of hypoxia on tumour radioresistance and
metastasis. Consequently, tumour hypoxia is a poor prog-
nostic factor in a number of malignancies6,129–131. several
molecular pathways that influence cellular metabolism
are altered under hypoxia. As described above, hypoxia
alters transcription through the stabilization of HIF,
which increases glycolytic capacity and decreases mito-
chondrial respiration132. In addition, and independently
of HIF, hypoxia inhibits signalling through mTOr, which
is a major regulator of multiple mechanisms contribut-
ing to the altered metabolic phenotype133,134. specifically,
the induction of autophagy may be of crucial impor-
tance135. Although mTOr inhibition would usually be
considered tumour suppressive, there is evidence that
in advanced malignancies such a response can increase
the tolerance to hypoxia and promote tumour cell sur-
vival during metabolic stress. This finding supports the
concept that, in certain microenvironmental or genetic
contexts, as in the case of rb inactivation, tumour cells
may benefit from retaining the ability to moderate
mTOr signalling 99. Finally, extreme hypoxia (<0.02% O2)
causes endoplasmic reticulum stress and activates the
unfolded protein response, which provides a further
adaptive mechanism that allows tumour cells to survive
under adverse metabolic conditions134,136–138.
Other metabolic stress conditions such as low pH
and low glucose are also prevalent in solid tumours and
are likely to be major determinants of the metabolic
phenotype. The molecular pathways that are involved
in responding to these conditions are currently under
investigation, which will undoubtedly enhance our
knowledge of the mechanistic determinants of tumour
cell metabolism. since it has been well established that
microenvironmental factors affect sensitivity to radia-
tion, traditional chemotherapy and targeted therapies,
a better understanding of the diverse avenues of meta-
bolic regulation in cancer cells may offer new oppor-
tunities to modify the tumour microenvironment for
therapeutic gain139.
It should be noted that the relationship between the
tumour microenvironment and cancer cell metabo-
lism is not one of simple cause and effect, in which
nATure revIeWs | CanCer
© 2011 Macmillan Publishers Limited. All rights reserved
REVIEWS
biochemical conditions in the tumour influence
cellular metabolism. because metabolite concentra-
tions are governed by both supply by the vasculature
and demand by the tissue, changes in metabolism of
both the tumour and normal stromal cells also have
a profound effect on microenvironmental condi-
tions (FIG. 1). The complex and dynamic relationship
between tumour metabolism and the microenviron-
ment emphasizes the importance of studying metabolic
regulation in vivo using appropriate model systems, as
well as the need for more sophisticated measurements
of cell metabolism and relevant microenvironmental
conditions in human tumours.
Metabolic flexibility. Although aerobic glycolysis (the
Warburg effect) is the best documented metabolic phe-
notype of tumour cells, it is not a universal feature of all
human cancers140. Moreover, even in glycolytic tumours,
oxidative phosphorylation is not completely shut down.
It is clear from both clinical FDG–PeT data, as well as
in vitro and in vivo experimental studies, that tumour
cells are capable of using alternative fuel sources. In fact,
up to 30% of tumours are considered FDG–PeT-negative
depending on the tumour type16,17. Amino acids, fatty
acids and even lactate have been shown to function as
fuels for tumour cells in certain genetic and microen-
vironmental contexts125,141,142. The carnitine palmitoyl-
transferase enzymes that regulate the β-oxidation of
fatty acids may have a key role in determining some
of these phenotypes. Furthermore, owing to the dynamic
nature of the tumour microenvironment, it is likely that
the metabolic phenotype of tumour cells changes to
adapt to the prevailing local conditions. The regulation
of this metabolic flexibility is poorly understood and will
require a much greater degree of understanding if effec-
tive therapeutic strategies targeting metabolism are to be
developed and effectively deployed.
Conclusion
Mutations in oncogenes and tumour suppressor genes
cause alterations to multiple intracellular signalling
pathways that affect tumour cell metabolism and re-
engineer it to allow enhanced survival and growth. In
fact, it is likely that metabolic alterations are required
for tumour cells to be able to respond to the prolifera-
tive signals that are delivered by oncogenic signalling
pathways. In addition, the unique biochemical microen-
vironment further influences the metabolic phenotype
of tumour cells, and thus affects tumour progres-
sion, response to therapy and patient outcome. These
metabolic adaptations must balance the three crucial
requirements of tumour cells: increased energy produc-
tion, sufficient macromolecular biosynthesis and main-
tenance of redox balance. Only by thoroughly dissecting
these processes will we discover the Achilles heels of
tumour metabolic pathways and be able to translate this
knowledge to the development and implementation of
novel classes of therapeutics. The ultimate goal is to
design treatment strategies that slow tumour progres-
sion, improve the response to therapy and result in a
positive clinical outcome.
vOluMe 11 | FebruAry 2011 | 93
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Acknowledgements
The authors would like to thank M. Saunders for scientific
editing of the Review.
Competing interests statement
The authors declare no competing financial interests.
DATABASES
National Cancer Institute Drug Dictionary:
http://www.cancer.gov/drugdictionary
l-asparaginase
Pathway Interaction Database: http://pid.nci.nih.gov
AMPK | HIF1 | HIF2 | LKB1 | mTOR | MYC | p53 | PI3K
FURTHER INFORMATION
Tak W. Mak’s homepage:
http://medbio.utoronto.ca/faculty/mak.html
all lInKS are aCtIve In tHe OnlIne PDf
vOluMe 11 | FebruAry 2011 | 95